HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium

So Ri Kim, Kyung Sun Lee, Hee Sun Park, Seoung Ju Park, Kyung Hoon Min, Hee Moon, Kamal D. Puri, Yong Chul Lee

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in immune and inflammatory responses. One of the HIF-1α target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA-treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF-1α activation and the role of HIF-1α in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1α siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1α and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1α inhibitor, 2-methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL-4, IL-5, IL-13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2-methoxyestradiol or a VEGF inhibitor, CBO-P11. Moreover, we found that inhibition of the PI3K p110d isoform (PI3K-δ) or HIF-1α reduced OVA-induced HIF-1α activation in airway epithelial cells. These findings indicate that HIF-1α inhibition may attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K-δ signaling may be involved in the allergen-induced HIF-1α activation.

Original languageEnglish
Pages (from-to)2858-2869
Number of pages12
JournalEuropean Journal of Immunology
Volume40
Issue number10
DOIs
Publication statusPublished - 2010 Oct

Keywords

  • Allergic airway disease
  • Hypoxia-inducible factor-1α
  • PI3K-δ
  • RNA interference
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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